A Novel Apolipoprotein E Antagonist Functionally Blocks Apolipoprotein E Interaction With N-terminal Amyloid Precursor Protein, Reduces β-Amyloid-Associated Pathology, and Improves Cognition.
Alzheimer Disease
/ metabolism
Amyloid beta-Protein Precursor
/ genetics
Animals
Apolipoproteins E
/ antagonists & inhibitors
Brain
/ pathology
CHO Cells
Cognition
/ drug effects
Cricetulus
Disease Models, Animal
Female
Humans
LDL-Receptor Related Protein-Associated Protein
/ metabolism
Male
Memory
/ drug effects
Mice
Mice, Transgenic
Acetylated and phosphorylated tau
Alzheimer’s disease
Alzheimer’s mouse model
Amyloid precursor protein
Amyloidogenesis
Apolipoprotein E
Low-density lipoprotein receptor binding domain
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 08 2019
01 08 2019
Historique:
received:
26
11
2018
revised:
21
03
2019
accepted:
15
04
2019
pubmed:
19
6
2019
medline:
5
8
2020
entrez:
19
6
2019
Statut:
ppublish
Résumé
The ɛ4 isoform of apolipoprotein E (apoE4) is a major genetic risk factor for the development of sporadic Alzheimer's disease (AD), and its modification has been an intense focus for treatment of AD during recent years. We investigated the binding of apoE, a peptide corresponding to its low-density lipoprotein receptor binding domain (amino acids 133-152; ApoEp), and modified ApoEp to amyloid precursor protein (APP) and their effects on amyloid-β (Aβ) production in cultured cells. Having discovered a peptide (6KApoEp) that blocks the interaction of apoE with N-terminal APP, we investigated the effects of this peptide and ApoEp on AD-like pathology and behavioral impairment in 3XTg-AD and 5XFAD transgenic mice. ApoE and ApoEp, but not truncated apoE lacking the low-density lipoprotein receptor binding domain, physically interacted with N-terminal APP and thereby mediated Aβ production. Interestingly, the addition of 6 lysine residues to the N-terminus of ApoEp (6KApoEp) directly inhibited apoE binding to N-terminal APP and markedly limited apoE- and ApoEp-mediated Aβ generation, presumably through decreasing APP cellular membrane trafficking and p44/42 mitogen-activated protein kinase phosphorylation. Moreover, while promoting apoE interaction with APP by ApoEp exacerbated Aβ and tau brain pathologies in 3XTg-AD mice, disrupting this interaction by 6KApoEp ameliorated cerebral Aβ and tau pathologies, neuronal apoptosis, synaptic loss, and hippocampal-dependent learning and memory impairment in 5XFAD mice without altering cholesterol, low-density lipoprotein receptor, and apoE expression levels. These data suggest that disrupting apoE interaction with N-terminal APP may be a novel disease-modifying therapeutic strategy for AD.
Sections du résumé
BACKGROUND
The ɛ4 isoform of apolipoprotein E (apoE4) is a major genetic risk factor for the development of sporadic Alzheimer's disease (AD), and its modification has been an intense focus for treatment of AD during recent years.
METHODS
We investigated the binding of apoE, a peptide corresponding to its low-density lipoprotein receptor binding domain (amino acids 133-152; ApoEp), and modified ApoEp to amyloid precursor protein (APP) and their effects on amyloid-β (Aβ) production in cultured cells. Having discovered a peptide (6KApoEp) that blocks the interaction of apoE with N-terminal APP, we investigated the effects of this peptide and ApoEp on AD-like pathology and behavioral impairment in 3XTg-AD and 5XFAD transgenic mice.
RESULTS
ApoE and ApoEp, but not truncated apoE lacking the low-density lipoprotein receptor binding domain, physically interacted with N-terminal APP and thereby mediated Aβ production. Interestingly, the addition of 6 lysine residues to the N-terminus of ApoEp (6KApoEp) directly inhibited apoE binding to N-terminal APP and markedly limited apoE- and ApoEp-mediated Aβ generation, presumably through decreasing APP cellular membrane trafficking and p44/42 mitogen-activated protein kinase phosphorylation. Moreover, while promoting apoE interaction with APP by ApoEp exacerbated Aβ and tau brain pathologies in 3XTg-AD mice, disrupting this interaction by 6KApoEp ameliorated cerebral Aβ and tau pathologies, neuronal apoptosis, synaptic loss, and hippocampal-dependent learning and memory impairment in 5XFAD mice without altering cholesterol, low-density lipoprotein receptor, and apoE expression levels.
CONCLUSIONS
These data suggest that disrupting apoE interaction with N-terminal APP may be a novel disease-modifying therapeutic strategy for AD.
Identifiants
pubmed: 31208706
pii: S0006-3223(19)31323-X
doi: 10.1016/j.biopsych.2019.04.026
pmc: PMC6642011
mid: NIHMS1528413
pii:
doi:
Substances chimiques
APP protein, human
0
Amyloid beta-Protein Precursor
0
ApoE protein, human
0
Apolipoproteins E
0
LDL-Receptor Related Protein-Associated Protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
208-220Subventions
Organisme : NIA NIH HHS
ID : R01 AG032432
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG050253
Pays : United States
Organisme : NCCIH NIH HHS
ID : R01 AT007411
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG049477
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Références
Biochem J. 2000 Jun 1;348 Pt 2:359-65
pubmed: 10816430
Physiol Rev. 2001 Apr;81(2):741-66
pubmed: 11274343
Science. 2002 Jul 19;297(5580):353-6
pubmed: 12130773
Int J Obes Relat Metab Disord. 2003 Feb;27(2):260-8
pubmed: 12587008
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10966-71
pubmed: 12939405
J Neurosci Res. 1992 Jun;32(2):227-38
pubmed: 1404494
J Neurosci. 2004 Mar 10;24(10):2527-34
pubmed: 15014128
J Neurosci. 2005 Sep 21;25(38):8807-14
pubmed: 16177050
J Am Chem Soc. 2005 Nov 2;127(43):15168-74
pubmed: 16248658
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18700-5
pubmed: 16344478
J Alzheimers Dis. 2006;9(3 Suppl):257-62
pubmed: 16914864
J Lipid Res. 2009 Apr;50 Suppl:S183-8
pubmed: 19106071
Nat Rev Neurosci. 2009 May;10(5):333-44
pubmed: 19339974
Lancet Neurol. 2011 Feb;10(2):187-98
pubmed: 21147038
J Neurosci. 2011 Jan 26;31(4):1355-65
pubmed: 21273420
Sci Transl Med. 2011 Jun 29;3(89):89ra57
pubmed: 21715678
Nature. 2011 Jul 13;475(7355):S20-2
pubmed: 21760580
Nat Commun. 2012 Apr 10;3:777
pubmed: 22491325
Alzheimers Res Ther. 2013 Oct 08;5(5):46
pubmed: 24103387
Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 2):2878-86
pubmed: 24183852
J Neurochem. 2014 Jun;129(5):756-69
pubmed: 24517464
Cell Death Dis. 2014 Aug 14;5:e1374
pubmed: 25118934
Trends Pharmacol Sci. 2016 May;37(5):390-411
pubmed: 26837733
J Neurosci Res. 2017 Apr;95(4):973-991
pubmed: 27531392
J Neuroimmunol. 2016 Oct 15;299:98-106
pubmed: 27725131
Cell. 2017 Jan 26;168(3):427-441.e21
pubmed: 28111074
Front Mol Neurosci. 2017 Jan 31;10:3
pubmed: 28197070
Heliyon. 2017 Apr 04;3(4):e00279
pubmed: 28413833
Biol Psychiatry. 2018 Feb 15;83(4):347-357
pubmed: 28434655
Prog Neurobiol. 2017 Sep;156:189-213
pubmed: 28587768
J Neurochem. 2017 Oct;143(1):11-29
pubmed: 28677143
Nature. 2017 Sep 28;549(7673):523-527
pubmed: 28959956
Mol Neurobiol. 2018 Jul;55(7):5809-5829
pubmed: 29079999
Nat Med. 2018 May;24(5):647-657
pubmed: 29632371
Mol Neurobiol. 2019 Apr;56(4):2450-2465
pubmed: 30032423
Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7
pubmed: 3088567
Science. 1988 Apr 29;240(4852):622-30
pubmed: 3283935
Ann Neurol. 1986 May;19(5):415-24
pubmed: 3717905
Biochem Biophys Res Commun. 1984 May 16;120(3):885-90
pubmed: 6375662
J Med Chem. 1995 Oct 13;38(21):4141-54
pubmed: 7473539
Nat Genet. 1995 Jan;9(1):21-30
pubmed: 7704018
Lancet. 1994 Aug 13;344(8920):473
pubmed: 7914580
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3270-4
pubmed: 8159737
Cell. 1993 Dec 17;75(6):1039-42
pubmed: 8261505
Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7951-5
pubmed: 8367446
Ann N Y Acad Sci. 1996 Jan 17;777:57-64
pubmed: 8624127
J Biol Chem. 1998 May 29;273(22):13892-7
pubmed: 9593736
J Exp Med. 1998 Aug 3;188(3):431-8
pubmed: 9687521
Brain Res. 1998 Oct 5;807(1-2):110-7
pubmed: 9757011